Bottom Line:
This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults.Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues.Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets.

ABSTRACTCells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, GO, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance.

Figure 3: Glutathione and TXN systemsGenes that are highly expressed in tumors versus normal tissues are highlighted in gray and those associated with bad prognosis in lung or breast cancer are highlighted in yellow. The redox state of proteins and metabolites is depicted in color (red=reduced and blue=oxidized). Metabolites are boxed and inhibitors are circled. This scheme is adapted from [137].

Mentions:
The thioredoxin system is highly conserved throughout evolution and we observed that multiple members of this system are highly overexpressed in multiple cancers (Figure 1; group 6) and confer dismal prognosis in lung and breast cancers (Table 1 and Figure S1-S3). TXN is a small protein that reduces oxidized proteins and supports peroxiredoxin (PRDX)-mediated H2O2 clearance (Figure 3) [21]. It also positively regulates the activity of PTP1B, the phosphatase of the tyrosine kinase PDGF-beta, leading to increased PDGF-beta signaling [20] and it negatively regulates the tumor suppressor PTEN [22, 23]. These functions point to an oncogenic role of TXN.

Figure 3: Glutathione and TXN systemsGenes that are highly expressed in tumors versus normal tissues are highlighted in gray and those associated with bad prognosis in lung or breast cancer are highlighted in yellow. The redox state of proteins and metabolites is depicted in color (red=reduced and blue=oxidized). Metabolites are boxed and inhibitors are circled. This scheme is adapted from [137].

Mentions:
The thioredoxin system is highly conserved throughout evolution and we observed that multiple members of this system are highly overexpressed in multiple cancers (Figure 1; group 6) and confer dismal prognosis in lung and breast cancers (Table 1 and Figure S1-S3). TXN is a small protein that reduces oxidized proteins and supports peroxiredoxin (PRDX)-mediated H2O2 clearance (Figure 3) [21]. It also positively regulates the activity of PTP1B, the phosphatase of the tyrosine kinase PDGF-beta, leading to increased PDGF-beta signaling [20] and it negatively regulates the tumor suppressor PTEN [22, 23]. These functions point to an oncogenic role of TXN.

Bottom Line:
This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults.Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues.Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets.

ABSTRACTCells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, GO, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance.